Maurizio Rossini

Department of Medicine, Section of Rheumatology, University of Verona

Dear Colleagues,

As you will see, this issue features two contributions relative to the debate on the possible extra skeletal effects of vitamin D supplementation, in particular on type-2 diabetes (T2DM) and in the field of cancer treatment. 

You will note that both authors correctly conclude that in general available trials have not found significant results on these fronts: rather, because they were conducted on populations which on the whole were not vitamin D deficient, they are not able to exclude a protective effect of vitamin D supplementation in subjects who are deficient, especially if we consider that sub-analyses of these subjects actually suggest a positive effect.

We see, for example, that a post-hoc analysis of the randomized clinical trial by Pittas et al. [1] on a small number of participants that had baseline circulating levels of 25-hydroxyvitamin D <12 ng/mL (< 30 nmol/L) showed that the risk of developing T2DM was reduced by 60% in subjects treated with cholecalciferol with respect to those given the placebo (hazard ratio [HR] 0.38, 95% IC 0.18-0.80).

We further find that in the study conducted on patients affected by lung tumors vitamin D supplementation did not on the whole produce the expected results. Yet when patients with early stage adenocarcinoma and low vitamin D levels were selected, supplementation in fact reduced mortality by over 60% with respect to the placebo (HR = 0.37; 95% IC 0.15-0.95). [2]

The time required to assess an outcome may also be fundamental: you will see, for example, that the negative conclusion of the VITAL trial [3] would change if the follow-ups of the first 1-2 years were excluded: such an exclusion, in my opinion, would be reasonable, given the biological latency. In that case, vitamin D supplementation shows a significant – 25% – reduction of death by cancer (HR = 0.75; 95% IC 0.59-0.96).

With regard to the documentation on a significant effect of vitamin D supplementation only in subjects with low baseline 25-hydroxyvitamin D3 levels, it is worth remembering that the literature contains numerous other examples, both skeletal and extra skeletal [4]. Figure 1 shows several examples of different effects of supplementation on some extra skeletal risks with respect to baseline serum levels – low and not low – in supplemented patients. 

This should not surprise us [5], in view of the fact that vitamin D acts as a nutrient: it is beneficial when lacking, though not so when it is not lacking…

To conclude, I do not believe that we can affirm today that we are overestimating the possible extra skeletal benefits of vitamin D supplementation. Neither do I think that we can deny them, given that the design and results of clinical trials conducted thus far do not allow us to exclude such benefits.

What do you think? 

I hope you enjoy reading this issue.

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